Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism

Julián Aragonés, Martin Schneider, Katie Van Geyte, Peter Fraisl, Tom Dresselaers, Massimiliano Mazzone, Ruud Dirkx, Serena Zacchigna, Hélène Lemieux, Nam Ho Jeoung, Diether Lambrechts, Tammie Bishop, Peggy Lafuste, Antonio Diez-Juan, Sarah K. Harten, Pieter Van Noten, Katrien De Bock, Carsten Willam, Marc Tjwa, Alexandra GrosfeldRachel Navet, Lieve Moons, Thierry Vandendriessche, Christophe Deroose, Bhathiya Wijeyekoon, Johan Nuyts, Benedicte Jordan, Robert Silasi-Mansat, Florea Lupu, Mieke Dewerchin, Chris Pugh, Phil Salmon, Luc Mortelmans, Bernard Gallez, Frans Gorus, Johan Buyse, Francis Sluse, Robert Harris, Erich Gnaiger, Peter Hespel, Paul Van Hecke, Frans Schuit, Paul Van Veldhoven, Peter Ratcliffe, Myriam Baes, Patrick Maxwell, Peter Carmeliet

Research output: Contribution to journalArticle

321 Citations (Scopus)

Abstract

HIF prolyl hydroxylases (PHD1-3) are oxygen sensors that regulate the stability of the hypoxia-inducible factors (HIFs) in an oxygen-dependent manner. Here, we show that loss of Phd1 lowers oxygen consumption in skeletal muscle by reprogramming glucose metabolism from oxidative to more anaerobic ATP production through activation of a Pparα pathway. This metabolic adaptation to oxygen conservation impairs oxidative muscle performance in healthy conditions, but it provides acute protection of myofibers against lethal ischemia. Hypoxia tolerance is not due to HIF-dependent angiogenesis, erythropoiesis or vasodilation, but rather to reduced generation of oxidative stress, which allows Phd1-deficient myofibers to preserve mitochondrial respiration. Hypoxia tolerance relies primarily on Hif-2α and was not observed in heterozygous Phd2-deficient or homozygous Phd3-deficient mice. Of medical importance, conditional knockdown of Phd1 also rapidly induces hypoxia tolerance. These findings delineate a new role of Phd1 in hypoxia tolerance and offer new treatment perspectives for disorders characterized by oxidative stress.

Original languageEnglish
Pages (from-to)170-180
Number of pages11
JournalNature Genetics
Volume40
Issue number2
DOIs
StatePublished - Feb 2008

Fingerprint

Basal Metabolism
Oxygen
Hypoxia-Inducible Factor-Proline Dioxygenases
Oxidative Stress
Angiogenesis Inducing Agents
Erythropoiesis
Vasodilation
Oxygen Consumption
Hypoxia
Respiration
Skeletal Muscle
Ischemia
Adenosine Triphosphate
Glucose
Muscles

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Aragonés, J., Schneider, M., Van Geyte, K., Fraisl, P., Dresselaers, T., Mazzone, M., ... Carmeliet, P. (2008). Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nature Genetics, 40(2), 170-180. https://doi.org/10.1038/ng.2007.62

Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. / Aragonés, Julián; Schneider, Martin; Van Geyte, Katie; Fraisl, Peter; Dresselaers, Tom; Mazzone, Massimiliano; Dirkx, Ruud; Zacchigna, Serena; Lemieux, Hélène; Jeoung, Nam Ho; Lambrechts, Diether; Bishop, Tammie; Lafuste, Peggy; Diez-Juan, Antonio; Harten, Sarah K.; Van Noten, Pieter; De Bock, Katrien; Willam, Carsten; Tjwa, Marc; Grosfeld, Alexandra; Navet, Rachel; Moons, Lieve; Vandendriessche, Thierry; Deroose, Christophe; Wijeyekoon, Bhathiya; Nuyts, Johan; Jordan, Benedicte; Silasi-Mansat, Robert; Lupu, Florea; Dewerchin, Mieke; Pugh, Chris; Salmon, Phil; Mortelmans, Luc; Gallez, Bernard; Gorus, Frans; Buyse, Johan; Sluse, Francis; Harris, Robert; Gnaiger, Erich; Hespel, Peter; Van Hecke, Paul; Schuit, Frans; Van Veldhoven, Paul; Ratcliffe, Peter; Baes, Myriam; Maxwell, Patrick; Carmeliet, Peter.

In: Nature Genetics, Vol. 40, No. 2, 02.2008, p. 170-180.

Research output: Contribution to journalArticle

Aragonés, J, Schneider, M, Van Geyte, K, Fraisl, P, Dresselaers, T, Mazzone, M, Dirkx, R, Zacchigna, S, Lemieux, H, Jeoung, NH, Lambrechts, D, Bishop, T, Lafuste, P, Diez-Juan, A, Harten, SK, Van Noten, P, De Bock, K, Willam, C, Tjwa, M, Grosfeld, A, Navet, R, Moons, L, Vandendriessche, T, Deroose, C, Wijeyekoon, B, Nuyts, J, Jordan, B, Silasi-Mansat, R, Lupu, F, Dewerchin, M, Pugh, C, Salmon, P, Mortelmans, L, Gallez, B, Gorus, F, Buyse, J, Sluse, F, Harris, R, Gnaiger, E, Hespel, P, Van Hecke, P, Schuit, F, Van Veldhoven, P, Ratcliffe, P, Baes, M, Maxwell, P & Carmeliet, P 2008, 'Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism', Nature Genetics, vol. 40, no. 2, pp. 170-180. https://doi.org/10.1038/ng.2007.62
Aragonés J, Schneider M, Van Geyte K, Fraisl P, Dresselaers T, Mazzone M et al. Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nature Genetics. 2008 Feb;40(2):170-180. https://doi.org/10.1038/ng.2007.62
Aragonés, Julián ; Schneider, Martin ; Van Geyte, Katie ; Fraisl, Peter ; Dresselaers, Tom ; Mazzone, Massimiliano ; Dirkx, Ruud ; Zacchigna, Serena ; Lemieux, Hélène ; Jeoung, Nam Ho ; Lambrechts, Diether ; Bishop, Tammie ; Lafuste, Peggy ; Diez-Juan, Antonio ; Harten, Sarah K. ; Van Noten, Pieter ; De Bock, Katrien ; Willam, Carsten ; Tjwa, Marc ; Grosfeld, Alexandra ; Navet, Rachel ; Moons, Lieve ; Vandendriessche, Thierry ; Deroose, Christophe ; Wijeyekoon, Bhathiya ; Nuyts, Johan ; Jordan, Benedicte ; Silasi-Mansat, Robert ; Lupu, Florea ; Dewerchin, Mieke ; Pugh, Chris ; Salmon, Phil ; Mortelmans, Luc ; Gallez, Bernard ; Gorus, Frans ; Buyse, Johan ; Sluse, Francis ; Harris, Robert ; Gnaiger, Erich ; Hespel, Peter ; Van Hecke, Paul ; Schuit, Frans ; Van Veldhoven, Paul ; Ratcliffe, Peter ; Baes, Myriam ; Maxwell, Patrick ; Carmeliet, Peter. / Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. In: Nature Genetics. 2008 ; Vol. 40, No. 2. pp. 170-180.
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